EP0687254A1

EP0687254A1 - 4-aminopyridines, their preparation and their use as antithrombotic agent

Info

Publication number: EP0687254A1
Application number: EP94910360A
Authority: EP
Inventors: Herbert Leinert; Wolfgang Von Der Saal; Karlheinz Stegmeier; Thomas Poll
Original assignee: Roche Diagnostics GmbH; Boehringer Mannheim GmbH
Current assignee: Roche Diagnostics GmbH
Priority date: 1993-03-05
Filing date: 1994-03-02
Publication date: 1995-12-20
Also published as: DE4306873A1; ZA941522B; IL108847A0; WO1994020468A1; JPH08509472A; AU6282494A; CA2157215A1

Abstract

Compounds of formula (i) in which R1 is an aryl, a heteroaryl or a cycloalkyl group which may, if desired, be substituted; AS is an amino-acid; n is 0 or 1; and R2 and R3 are the same or different and represent hydrogen atoms, alkyl, carboxy, alkyl or alkoxy carbonyl alkyl groups, or R2 and R3, together with the nitrogen atom to which they are bonded, form a heterocyclyl ring which may if desired also contain a second heteroatom and be substituted by alkyl, carboxy or alkoxy carbonyl groups; R4 and R5 are the same or different and are hydrogen atoms or alkyl groups; m^_ is 0, 1 or 2; R6, R7, R8 and R9 are the same or different and are hydrogen or halogen atoms; and hydrates, solvates and physiological acceptable salts thereof. The invention also relates to the optically active forms, the racemates and the diastereomer mixtures of these compounds and a process for their production and medicaments containing these compounds, especially a process for the production of medicaments for the treatment of thrombo-embolic diseases.

Description

--Am1πopyr1d1πe, your production and use as a s aπt1thrombot1 means

The invention relates to new 4-aminopyridines of the general formula I.

in the

R .. an aryl, a heteroaryl or a cycioalkyl group, which can be substituted if desired,

AS an amino acid,

n the numbers 0 or 1,

R ₂ and R «are identical or different and form hydrogen atoms, alkyl, carboxyalkyl or alkoxycarbonylalkyl groups or R ₂ and R ₃ together with the nitrogen atom to which they are attached form a heterocyclyl ring which, if desired, also contains a second hetero atom and can be substituted by alkyl, carboxy or alkoxycarbonyl groups,

R ₄ and R _{5 are} identical or different and are hydrogen atoms or alkyl groups, m the numbers 0, 1 or 2,

Rg, R7, Rδ and Rg are the same or different and denote hydrogen atoms or halogen atoms,

and hydrates, solvates and physiologically acceptable salts thereof. The invention also relates to the optically active forms, the racemates and the diastereomer mixtures of these compounds.

The invention also relates to processes for the preparation of the above compounds, medicaments containing such compounds and the use of these compounds in the production of medicaments.

The aminopyridines of the general formula I, their solvates and their salts inhibit both the thrombin-induced clotting of fibrinogen in the blood and the thrombin-induced aggregation of the blood platelets. They prevent the formation of coagulation thrombi and platelet-rich thrombi and can be used to combat and prevent diseases such as thrombosis, apoplexy, heart attack, inflammation and arteriosclerosis. These compounds also have an effect on tumor cells and prevent the formation of metastases. Thus, they can be used as anti-tumor agents.

Thrombin, the last enzyme in the coagulation cascade, cleaves fibrinogen to fibrin, which is cross-linked by the Xllla factor and becomes an insoluble gel that forms the matrix for a thrombus. Thrombin activates platelet aggregation by proteolysis of its receptor on the blood platelets and in this way also contributes to thrombus formation. If a blood vessel is injured, these processes are necessary to stop bleeding. Under normal circumstances, there are no measurable thrombin concentrations in the blood plasma. Increasing thrombin concentration can lead to the formation of thrombi and thus to thromboembolic diseases, which occur very frequently, especially in the industrialized countries.

Thrombin is kept in the form of prothrombin in the plasma and released by factor Xa. Thrombin activates factor VIII, which then converts factor X to factor Xa with factor IXa. Thrombin thereby catalyzes its own release, which is why thrombin concentrations can increase very rapidly.

Thrombin inhibitors can therefore inhibit the release of thrombin, platelet-induced and plasmatic blood coagulation.

In addition to thrombin, there are a whole series of serine proteases that cleave peptide substrates in addition to a basic amino acid. To minimize side effects, the thrombin inhibitors should be selective, i.e. H. they should inhibit other serine proteases only slightly or not at all. Trypsin in particular, as the most unspecific serine protease, can be easily inhibited by a wide variety of inhibitors. Trypsin inhibition can lead to pancreatic stimulation and to pancreatic hypertrophy (J.D. Geratz, Am. J. Physiol. 216, (1969) p. 812).

Plasma contains the protein plasminogen, which is converted into plasmin by activators. Plasmin is a proteolytic enzyme whose activity is similar to that of trypsin. It serves to dissolve the thrombus by breaking down fibrin. Inhibition of the plasmin would therefore have exactly the opposite effect which one would like to achieve by inhibiting the thrombin.

Synthetic thrombin inhibitors have long been known. Starting from fibrinogen, the natural substrate of thrombin, substances of the (D) -Phe-Pro-Arg type were synthesized. Such tripeptides mimic the amino acid sequence before the cleavage site on the fibrinogen. In order to obtain good inhibitors, the carboxylate group of the arginine was changed so that the hydroxyl group of the serine-195 of the active site of the thrombin can react with it. This is possible, for example, by replacing the carboxylate group with the aldehyde function. Corresponding (D) -Phe-Pro-Arginale are described in the patent application EP-A-185390.

For a second type of thrombin inhibitor, the benzamidine known as the trypsin inhibitor was used as the basis. The inhibitors obtained in this way differ from the (D) - Phe-Pro-Arg types not only in their chemical structure, but also in the type of inhibition: the serine-195 of thrombin does not bind to these inhibitors. This is clearly evident from X-ray structure examinations. before (W. Bode, D. Turk, J. Sturzbecher, Eur. J. Biochem. 193, 175-182 (1990)). This second class of thrombin inhibitors includes N- (2-naphthylsulfonylglycyl) -4-amidino- (R, S) -phenylalanine piperidide ("NAPAP", DD 235866).

A disadvantage of the inhibitors of the (D) -Phe-Pro-Arg class is the lack of selectivity towards other serine proteases (JC Powers, C.-M. Kam, in Thrombin, Structure and Function (LJ Berliner, editor), plenum , New York 1992, p.117). Selectivity is slightly better with NAPAP. The inhibition constants of NAPAP are as follows (J. Sturzbecher et al., Pharmazie 34 (1988), p. 782): thrombin 6 nM, trypsin 0.69 μM, plasmin 30 μM. The selectivity of this inhibitor between thrombin and trypsin, expressed as the quotient of the inhibition constant, is therefore about 1: 100. The greatest disadvantage of these inhibitors is to be found in the fact that after oral administration they do not reach the place of action, the blood stream, or only insufficiently. The main reason for this deficiency is the strong basicity of the inhibitors. Since thrombin selectively recognizes the amino acid arginine, it is not surprising that the inhibitors also contain groups with a basicity similar to that of the guanidino group of the arginine. The pKa value of the side chain of arginine is 12.5 (D. Voet, JGVoet, Biochemie, VCH-Verlag Weinheim 1992, p.60), the pKa value of benzamidine is 11.8 (Albert, J. Chem. Soc. 1948, 2240).

There has been no lack of effort to develop thrombin inhibitors with less basic groups to improve oral availability. For example, Sturzbecher et al (loc.cit.) Established a connection that differs from NAPAP only in that the benzamidino group is replaced by a benzylamino group. Benzylamine has a significantly reduced basicity compared to benzamidine: pKa = 9.35 (Robinson, Trans. Faraday Soc. 52 (1956), 327). Due to this change in NAPAP, however, the inhibitory effect on thrombin dropped by several orders of magnitude to Ki = 19 μM and the selectivity thrombin / trypsin was only 1: 4, i.e. it almost completely disappeared.

Surprisingly, it has now been found that 4-aminopyridines of the general formula I are strong and selective thrombin inhibitors, although the 4-aminopyridine with pKa = 9.29 (JMEssen, K. Schofield, J. Chem. Soc. 1961, 3939) is a similarly low one Has basicity like benzylamine. This not only improves oral availability, but also tolerance is also improved and the drop in blood pressure observed with the NAPAP derivatives is reduced.

In general formula I one understands R- | the phenyl, naphthyl and anthryl group, if desired with 1-5 identical or different substituents such as halogen, nitro, nitrile, phenyl, cyclopropyl, cyclopentyl, cyclohexyl, cycloheptyl, trifluoromethyl, trrfluoromethoxy, C- | -C8 alkyl, C ^ Cg alkenyl, C _j -Cg alkynyl, hydroxy, C ^ Cg alkyloxy, C ^ Cg alkenyloxy, C, -Cg alkynyloxy, amino, C.-Cg-alkylamino-, C ^ -Cg-alkenylamino-, C -.- Cg-alkynylamino-, di- (C ^ -C ₈ -alkyl) amino-, benzylamino-, dibenzylamino-, carboxyl-, C ^ -C ₈ - alkyloxy-carbonyl-, aminocarbonyl-, C.-Cg-alkylaminocarbonyl-, di- (C- | -C8-alkyl) amino-carbonyl-, C -.- Cg-alkylthio-, C ^ -Cg- Alkylsulfinyl-, C ^ Cg-Alkylsulfonyi- or C ^ Cg-Alkylsulfonylamino- may be substituted. The phenyl groups can be condensed with a cycloalkyl or heterocyclyl group, the tetrahydronaphthyl, indanyl, chromanyl, methylenedioxyphenyl, ethylenedioxyphenyl and tetrahydroquinolinyl groups being particularly preferred.

Heteroaryl for R ,, means five- and six-membered aromatics with 1-4 heteroatoms such as nitrogen, oxygen or sulfur, which can be condensed with one or two phenyl groups and whose carbon atoms, if desired, substituents such as halogen, nitro, nitrile, phenyl , Trifluoromethyl-, C _j -Cg-alkyl-, C _j -Cg-alkenyl-, C ^ Cg-alkynyl-, hydroxy-, C- _J -Cg-alkyloxy-, C _j -Cg-alkenyloxy-, C _j - Cg-alkynyloxy, amino, C ^ Cg-alkylamino, C _j -CG-alkenylamino, Ci-CSS alkynylamino, di- (C ..- Cg-alkyl) amino, benzylamino, carboxyl, Ci-Cβ-alkyloxy-carbonyl-, aminocarbonyl-, C ^ Cg-alkylaminocarbonyl-, di- (Cι-C8-alkyl) amino-carbonyl-, C _j -Cg-alkylthio-, C _j -Cg-alkylsulfinyl-, C _j -Cg-alkylsulfonyl- or C ^ Cg-alkylsulfonylamino- can wear. Preferred aromatics are furan, thiophene, pyrrole, oxazole, isoxazole, thiazole, isothiazole, imidazole, pyrazole, triazole, tetrazole, pyridine, pyrazine, pyrimidine, pyridazine, triazine, tetrazine, benzothiophene, dibenzothiophene, benzimidazole or carbazole.

The C.-Cg components mentioned can be straight-chain or branched. These are preferably to be understood as the methyl, ethyl, propyl, isopropyl, butyl, isobutyl, tert-butyl, pentyl, vinyl, allyl and propargyl radicals. Cycloalkyl groups for R. are rings with 3-8 C atoms, preferably the cyclopentyl, cyclohexyl and cycloheptyl group. In the general formula I, AS means glycine, azaglycine and the amino acids alanine, valine, leucine, isoleucine, methionine, proline, phenylalanine, tryptophane, serine, threonine, asparagine, aspartic acid, glutamine, glutamic acid, tyrosine , Cysteine, lysine, arginine and histidine, which can be in the D or L form or as a mixture of both forms.

If R ₁ and R ₃ form a heterocyclyl ring together with the nitrogen atom to which they are attached, this is preferably understood to mean pyrrolidine, piperidine, homopiperidine, piparazine, morpholine and thiomorpholine. These rings can carry one or two C.-Cg-alkyl, carboxyl or C.-Cg-alkyloxycarbonyl groups.

R <1 means in particular a phenyl, naphthyl, tetrahydronaphthyl, pyridinyl, thienyl, cyclohexyl or chromanyl ring which can be substituted one or more times by C 1 -C 6 -alkyl, C 1 -C 6 -alkoxy or halogen groups .

AS means in particular glycine, azaglycine, alanine, glutamine, glutamate, asparagine or aspartate.

n means in particular the numbers 0 or 1.

R ₁ and R ₃ can be the same or different and in particular mean a C 1 -C 6 -alkyl group, such as, for example, the ethyl group; a C- | -C6-alkoxycarbonyl-C- | -C6- alkyl group such as ethoxycarbonylmethyl; or a carboxy-Ci-Cß-alkyl group, such as carboxymethyl; or together with the N atom to which they are bound form a pyrrolidine, piperidine, homopiperidine, morpholine, thiomorpholine or piperazine ring which is optionally substituted by one or two C 1 -C 6 -alkyl groups, such as, for example, methyl , Ethyl, propyl or butyl; Carboxyl; or by C- | - Cß-alkoxycarbonyl, such as methoxycarbonyl, ethoxycarbonyl or tert. Butyloxycarbonyl.

R ₄ and R ₅ can be the same or different and in particular represent hydrogen atoms or C 1 -C 6 -alkyl groups, preferably methyl groups.

Rg, R, Rg, R _g can be the same or different and in particular represent hydrogen, fluorine or chlorine atoms. Compounds of the general formula I in which

R ₁ phenyl, 4-methylphenyl, 4-chlorophenyl, 4-methoxyphenyl, 1-naphthyl,

2-naphthyl, 5,6,7,8-tetrahydro-2-naphthyl, 3-pyridinyl, 2-thienyl, cyclohexyl, 2,2,5,7,8-pentamethyl-chroman-6-yl or 4-methoxy- 2,3,6-trimethylphenyl means

AS means glycine, azaglycine or alanine, glutamine, glutamate, asparagine or aspartate,

n can be the numbers 0 or 1,

R ₂ and R _{3 are the} same or different and are ethyl, ethoxycarbonylmethyl or carboxymethyl or, together with the N atom to which they are bound, a pyrrolidine, piperidine, homopiperidine, morpholine, thiomorpholine or piperazine ring form, optionally one or two methyl, ethyl, propyl, butyl, carboxyl, methoxycarbonyl, ethoxycarbonyl or tert. Can carry butyloxy-carbonyl groups,

R. and R _{c are} identical or different and denote hydrogen atoms or methyl groups,

Rg, R, Rg, Rg are the same or different and denote hydrogen, fluorine or chlorine atoms.

The physiologically tolerated salts of the compounds of the general formula I are formates, acetates, caproates, oleates, lactates, or salts of carboxylic acids with up to 16 C atoms, hydrochlorides, hydrobromides, hydroiodides, alakanesulfonates with up to 10 C atoms, Salts of dicarboxylic acids and tricarboxylic acids such as citrates, malonates and tartrates.

The compounds of general formula I, in which R. ₁ -R5. AS, n and m have the abovementioned meanings and Rg-Rg represent halogen, are shown in which a compound of the general formula II,

in the R- ₁ -R5. AS, n and m have the meanings given above, with a compound of the general formula III,

in which Rg-R _{g represent} halogen, brings about the reaction.

The compounds of general formula I in which RiR _c . AS, n and m have the abovementioned meanings and Rg-Rg are hydrogen are represented by using a compound of the general formula I in which - _c - AS, n and m have the meanings given and Rg-Rg Halogen means subjected to a dehalogenation reaction.

The compounds of the general formula II in which R- ₁ -R5. AS, n and m have the meanings given above, are shown in which a compound of the general formula IV,

See in which R - _j - R _e - AS, n and m have the abovementioned meanings and Seh represents a protective group such as the benzyloxycarbonyl, t-butoxycarbonyl or the phthalimido group, with which it reacts with a reagent which splits off the protective groups.

The compounds of the general formula IV can be prepared by

in which m, n and Seh have the meanings given, with an amine of the general formula VI,

HN - Ra

(VI), R ₃

in which R ₂ and Rg have the meanings given, brings about the reaction and the resulting compounds of the general formula VII,

H ₂ N

See

in which R ₂ , Rg, Seh and m have the meanings given, with a compound of the general formula VIII (VIII),

in which R. has the meaning given and X represents either a halogen atom or a radical of the general formula IX,

HN - ( ^{| χ} ).

Y

in which Y is a halogen atom or an activated radical customary in peptide chemistry and A is a nitrogen atom or an atomic group of the general formula X

CH <* ^{* ■}

mean, wherein R _{1 Q represents} one of the usual amino acid side chain.

The compounds of the general formula V are prepared by processes known from the literature.

The compounds of general formula I can also be prepared by using a compound of general formula XI,

in which R ₂ -R _g and m have the meanings given, with a compound of the general formula VIII to react.

The compounds of general formula XI are prepared by using a compound of general formula XII,

in which R ₂ -R _{g have} the meanings given and Seh means a protective group which is customary in peptide chemistry, such as the benzyloxycarbonyl, t-butoxycarbonyl or phthalimide radical, is reacted with a reagent which cleaves the protective groups and is customary in peptide chemistry.

The compounds of the general formula XII are obtained by a compound of the general formula XIII,

in which R0-R5- ^and deh have the meanings given, with a compound of the general formula III to react.

The compounds of general formula XIII are prepared by combining the amide group with a compound of general formula XIV, in which R ₂ -R _c , Seh and m have the meanings given, subject to a Hofmann degradation.

The compounds of general formula XIV are prepared by using a compound of general formula XV,

in which R ₄ , Rc, Seh and m have the meanings given, reacted with a compound of the general formula VI.

The compounds of the general formula -XV are prepared from compounds of the general formula XVI,

in which R ₄ and R _{c have} the meanings given, by reaction with a protective group reagent customary in peptide chemistry.

The compounds of the general formula XVI are known in the literature. The reactions of a compound of general formula II with a compound of general formula III to a compound of general formula I are carried out in an inert solvent such as dimethylformamide, dioxane, dimethyl sulfoxide or toluene at temperatures between 0 degrees Celsius and boiling point of the solvent , preferably at room temperature in the presence of an auxiliary base such as triethylamine, N-methylmorpholine, pyridine or N-ethyldi-isopropylamine.

The compounds of the general formula I in which Rg-Rg are hydrogen, from the compounds of the general formula I in which Rg-Rg are halogen, are obtained from these by catalytic hydrogenation in an inert solvent such as e.g. Methanol or ethanol in the presence of an acid binding agent such as e.g. Sodium methylate or sodium ethylate preferably at room temperature and normal pressure with platinum or palladium as the catalyst.

The compounds of the general formula II are prepared by splitting off a protective group from the compounds of the general formula IV in accordance with the methods customary in peptide chemistry by acidic reagents such as e.g. Bromwas¬ hydrogen in glacial acetic acid, trifluoroacetic acid or hydrogenolytically or by cleavage with hydrazine.

The compounds of the general formula V are prepared by methods known from the literature, e.g. from an amino acid precursor with phosgene in an inert solvent such as e.g. Dioxane.

The reaction of compounds of general formula V to compounds of general formula IV is also carried out according to methods known in the literature in an inert solvent such as e.g. Dimethylformamide at temperatures between -50 and +50 degrees Celsius.

The reaction of compounds of general formula XI with compounds of general formula VIII to compounds of general formula I is carried out in an inert solvent such as dimethylformamide, methylene chloride or dioxane at temperatures between 0 and 50 degrees Celsius, preferably at room temperature in the presence of an auxiliary base such as Triethylamine, N-methyl-morpholine or N-ethyl-diisopropylamine. The amino protective group is split off from a compound of the general formula XII to a compound of the general formula XI, for example, hydrolytically using a solution of hydrogen bromide in glacial acetic acid, trifluoroacetic acid, hydrogenolytically or by reaction with hydrazine by customary methods known in peptide chemistry.

The reaction of a compound of general formula XIII with a compound of general formula III to a compound of general formula XII is carried out in an inert solvent such as e.g. Dimethylformamide, dioxane, dimethyl sulfoxide or toluene at temperatures between 0 degrees Celsius and the boiling point of the solvent, preferably at room temperature in the presence of an auxiliary base such as e.g. Triethylamine, N-methyl-morpholine, pyridine or N-ethyl-diisopropylamine.

The conversion of compounds of the general formula XIV into compounds of the general formula XIII is carried out by Hofmann degradation, preferably using [bis (trifluoroacetoxy) iodo] benzene in a mixture of an inert solvent with water, preferably in an acetonitrile / water mixture, preferably at room temperature.

The compounds of the general formula XIV are prepared from compounds of the general formula XV by methods customary in peptide chemistry.

The compounds of the general formula XV are also prepared from the compounds of the general formula XVI by methods customary in peptide chemistry.

The compounds of the general formula XVI are known in the literature.

Examples of physiologically usable salts of the compounds of the formula I are salts with physiologically tolerable mineral acids, such as hydrochloric acid, sulfuric acid, sulfurous acid or phosphoric acid; or with organic acids, such as methanesulfonic acid, p-toluenesulfonic acid, acetic acid, trifluoroacetic acid, citric acid, fumaric acid, maleic acid, tartaric acid, succinic acid or salicylic acid. The compounds of formula I with a free carboxy group can also form salts with physiologically compatible bases. Examples of such salts are alkali metal, earth alkali metal, ammonium and alkylammonium salts such as the Na, K, Ca or tetramethylammonium salt.

The compounds of the formula I can be solvated, in particular hydrated. The hydration can take place in the course of the production process or can gradually occur as a result of hygroscopic properties of an initially water-free compound of the formula I.

Pure enantiomers of the compounds of the formula I are obtained either by racemate resolution (via salt formation with optically active bases) or by using optically active starting materials in the synthesis.

For the production of pharmaceuticals, the substances of the general formula I are mixed with suitable pharmaceutical carriers, flavoring, flavoring and coloring agents and shaped, for example, as tablets or dragées or with the addition of appropriate auxiliaries in water or oil, e.g. in olive oil, suspended or dissolved.

The substances of the general formula I and their salts can be administered enterally or parenterally in liquid or solid form. Water is preferably used as the injection medium, which contains the additives customary for injection solutions, such as stabilizing agents, solubilizers or buffers. Such additives are e.g. Tartrate and citrate buffers, complexing agents (such as ethylenediaminetetraacetic acid and its non-toxic salts) and high molecular weight polymers such as liquid polyethylene oxide for viscosity regulation. Solid carriers are e.g. Starch, lactose, mannitol, methyl cellulose, talc, highly disperse silicas, high molecular fatty acids (such as stearic acid), animal and vegetable fats and solid high molecular polymers (such as polyethylene glycols). Preparations suitable for oral administration can, if desired, contain flavorings and sweeteners.

The compounds are usually applied in amounts of 10-1500 mg per day based on 75 kg of body weight. It is preferred to administer 1-2 tablets with an active substance content of 5-500 mg 2-3 times a day. The tablets can also be delayed, which means that only 1-2 tablets with 20-700 mg of active ingredient have to be given once a day. The active substance can also be injected tion are given 1-8 times a day or by continuous infusion, with 50-2000 mg per day usually being sufficient.

In addition to the compounds mentioned in the examples, the following are preferred for the purposes of the invention:

1. (R) -N-α- (2-naphthylsulfonylglycyl) -N- - (4-pyridinyl) -α, γ-di-aminobutyric acid homopiperidide

2. (R) -N-α- (2-naphthylsulfonylglycyl) -N * ^ - (4-pyridinyl) -α, γ-di-aminobutyric acid-4-methylpiperazide

3. (R) -N-α- (2-naphthylsulfonylglycyl) -N-γ- (4-pyridinyl) -α, γ-di-aminobutyric acid thiomorpholide

4. (R) -N-α- (2-naphthylsulfonylglycyl) -N-γ- (4-pyridinyl) -α, γ-di-aminobutyric acid (N-ethyl-N-ethoxycarbonylmethyl) amide

5. (R) -N- - (2-naphthylsulfonylglycyl) -N-g- (4-pyridinyl) -α, γ-di-aminobutyric acid- (N-ethyl-N-carboxymethyl) amide

6. (R) -N-α- (2-naphthylsulfonylazaglycycl) -N-γ- (4-pyridinyl) -α, γ-diaminobutyric acid homopiperidide

7. (R) -N-α- (4-methoxy-2,3,6-trimethylphenylsulfonylglycyl) -N-γ- (4-pyridinyl) -α, γ-diaminobutyric acid homopiperidide

8. (R) -N-α- (4-methoxy-2,3,6-trimethylphenylsulfonylazaglycyl) -N-γ- (4-pyridinyl) - α, γ-diaminobutyric acid piperidide

9. (R) -N-α- (2,2,5,7,8-pentamethyl-6-chromanylsulfonylglycyl) -N-γ- (4-pyridinyl) - α, γ-diaminobutyric acid homopiperidide

10. (R) -N-α- (2,2,5,7,8-pentamethyl-6-chromanyisulfonylazaglycyl) -N-γ- (4-pyridinyl) -α, γ-diaminobutyric acid piperidide 11. (R) -N-α- (5,6,7,8-tetrahydronaphthylsulfonylglycyl) -N-γ- (4-pyridinyl) - α, γ-diamino-butyric acid homopiperidide

12. (R) -N-α- (5,6,7,8-tetrahydronaphthylsulfonylazaglycyi) -N-γ- (4-pyridinyl) - α, γ-diaminobutyric acid piperidide

13. (R) -N-α- (2-naphthylsulfonyl- (S) -asparagyl) -N- ^ y- (4-pyridinyl) -α, γ-diaminobutyric acid homopiperidide

14. (R) -N-α- (5,6,7,8-tetrahydronaphthylsulfonyl- (S) -asparagyl) -N-γ- (4-pyridinyl) - α, γ-diaminobutyric acid piperidide

15. (R) -N- - (2,2,5,7,8-pentamethyl-6-chromanylsulfonyl- (S) -asparagyl) -N * ^ - (4-pyridinyl) -α, γ-diaminobutyric acid piperidide

16. (R) -N-α- (4-methoxy-2,3,6-trimethylphenyisulfonyl- (S) -asparagyl) -N-γ- (4-pyridinyl) -α, γ-diaminobutyric acid piperidide

17. (R) -N-α- (5,6,7,8-tetrahydronaphthylsulfonyl- (S) -asparagyl) -N - y- (4-pyridinyl) - α, γ-diaminobutyric acid homopiperidide

18. (R) -N-α- (2,2,5,7,8-pentamethyl-6-chromanyisulfonyl- (S) -asparagyl) -N-γ- (4-pyridinyl) -α, γ-diaminobutyric acid- homopiperidide

19. (R) -N-α- (4-methoxy-2,3,6-trimethylphenyisulfonyl- (S) -asparagyl) -N-γ- (4-pyridinyl) -α, γ-diaminobutyric acid homopiperidide

20. (R) -N-α- (2-naphthylsulfonyl- (S) -glutamyl) -N- ^ y- (4-pyridinyl) -α, γ-diamino-butyric acid piperidide

21. (R) -N-α- (2-naphthylsulfonyl- (S) -glutamyi) -N-γ- (4-pyridinyl) -α, γ-diamino-butyric acid homopiperidide

22. (R) -N-α- (5,6,7,8-tetrahydronaphthylsuifonyl- (S) -glutamyl) -Ny- (4-pyridinyl) - α, γ-diaminobutyric acid piperidide 23. (R) -N-α- (2,2,5,7,8-pentamethyl-6-chromanylsulfonyl- (S) -glutamyl) -N * -y- (4-pyridinyl) -α, γ-diaminobutyric acid -piperidide

24. (R) -N- - (4-methoxy-2,3,6-trimethylphenylsulfonyl- (S) -glutamyl) -N-γ- (4-pyridinyl) -α, γ-diaminobutyric acid piperidide

25. (R) -N-α- (5,6,7,8-tetrahydronaphthylsulfonyl- (S) -glutamyl) -N-y- (4-pyridinyl) - α, γ-diaminobutyric acid homopiperidide

26. (R) -N-α- (2,2,5,7,8-pentamethyl-6-chromanylsulfonyl- (S) -glutamyl) -N - y- (4-pyridinyl) -α, γ-diaminobutyric acid -homopiperidide

27. (R) -N-α- (4-methoxy-2,3,6-trimethylphenylsulfonyl- (S) -glutamyl) -N-γ- (4-pyridinyl) -α, γ-diaminobutyric acid homopiperidide

28. (R, S) -N-α- (2-naphthylsulfonyiglycyl) -N-β- (4-pyridinyl) -α, β-di-amino-propionic acid homopiperidide

29. (R, S) -N-α- (2-naphthylsifonylglycyl) -N-β- (4-pyridinyl) -α, β-di-amino-propionic acid-4-methylpiperidide

30. (R, S) -N-α- (2-naphthylsulfonylglycyl) -N-β- (4-pyridinyl) -α, β-di-amino-propionic acid-2-carboxypiperidide

31. (R, S) -N-α- (2-naphthylsulfonylglycyl) -N-β- (4-pyridinyl) -α, β-di-amino-propionic acid-3-carboxypiperidide

32. (R, S) -N-α- (2-Naphthylsulfonyiglycyl) -N-β- (4-pyridinyl) -α, β-di-amino-propionic acid-4-carboxypiperidide

33. (R, S) -N-α- (2-naphthyisulfonylglycyl) -N-β- (4-pyridinyl) -α, β-di-amino-propionic acid-2-carboxypyrrolidide

34. (R, S) -N-α- (5,6,7,8-tetrahydronaphthylsulfonylglycyl) -N-β- (4-pyridinyl) - α, β-diaminopropionic acid piperidide 35. (R, S) -N-α- (5,6,7,8-tetrahydronaphthylsulfonylglycyl) -N-β- (4-pyridinyl) - α, β-diaminopropionic acid-4-methylpiperidide

36. (R, S) -N-α- (5,6,7,8-tetrahydronaphthylsulfonylglycyl) -N-β- (4-pyridinyl) - α, β-diaminopropionic acid-2-carboxypiperidide

37. (R) -N-α- (5,6,7,8-tetrahydronaphthylsulfonylglycyl) -N-β- (4-pyridinyl) -α, β-diaminopropionic acid-2-carboxypyrrolidide

38. (R, S) -N-α- (2,2,5,7,8-pentamethyl-6-chromanylsulfonylglycyl) -N-β- (4-pyridinyl) - α, β-diaminopropionic acid piperidide

39. (R, S) -N-α- (2,2,5,7,8-pentamethyl-6-chromanylsulfonylglycyl) -N-β- (4-pyridinyl) - α, β-diaminopropionic acid-4-methylpiperidide

40. (R, S) -N-α- (2,2,5,7,8-pentamethyl-6-chromanylsulfonylglycyl) -N-β- (4-pyridinyl) - α, β-diaminopropionic acid-2-carboxypiperidide

41. (R, S) -N-α- (2,2,5,7,8-pentamethyl-6-chromanylsulfonylglycyl) -N-β- (4-pyridinyl) - α, β-diaminopropionic acid-2-carboxypyrrolidide

42. (R, S) -N-α- (4-methoxy-2,3,6-trimethylphenylsulfonylglycyl) -N-β- (4-pyridinyl) -, β-diaminopropionic acid piperidide

43. (R, S) -N-α- (4-methoxy-2,3,6-trimethyiphenyisulfonylglycyl) -N-β- (4-pyridinyl) -, β-diaminopropionic acid-4-methylpiperidide

44. (R, S) -N-α- (4-methoxy-2,3,6-trimethylphenylsulfonylglycyl) -N-β- (4-pyridinyl) - α, β-diaminopropionic acid-2-carboxypiperidide

45. (R, S) -N-α- (4-methoxy-2,3,6-trimethylphenylsuifonylglycyl) -N-β- (4-pyridinyl) - α, β-diaminopropionic acid-2-carboxypyrrolidide example 1

(R.S) -N-α- (2-naphthylsulfonylqlvcyl) -N * ^ - (2,3,5,6-tetra-chloropyridine * -4-vn-α, γ-diaminobutyric acid piperidide

1. (R.S) -N-α- (2-naphthylsulfonylαlvcyl) -v-phthalimido-α-aminobutyric acid piperidide

A solution of 4.6 g of (R, S) -4-ß-phthalimidoethyloxazolidin-2,5-dione in 22 ml of absolute. Dimethylformamide is cooled to -50 degrees Celsius. A solution of 1.7 ml of piperidine and 2 ml of N-methylmorpholine in 22 ml of absolute is added dropwise with stirring over the course of 15 minutes. Dimethylformamide. The mixture is stirred for a further 30 minutes and then the reaction mixture is heated to 60 degrees Celsius for 30 minutes. The mixture is cooled to room temperature and a solution of 4.5 g of 2Naphthylsulfonyl-glycyl chloride in 20 ml of absolute is added dropwise while stirring. Methylene chloride too. The mixture is stirred for a further 2 hours at room temperature and then evaporated in vacuo. on. The residue is dissolved in methylene chloride and the solution washed with water. The methylene chloride phase is dried over sodium sulfate and evaporated. The residue is purified by chromatography on a silica gel column (mobile phase: acetone / toluene 1: 1). After evaporation of the corresponding column fractions, 4.5 g of the title compound are obtained as an amorphous substance.

2. (R.S) -N-α- (2-naphthylsulfonylqlvcyl) -α, γ-diaminobutyric acid piperidide

4.5 g of (R, S) -N-α- (2-naphthylsulfonylglycyl) -phthalimido-α-aminobutyric acid piperidide are dissolved in 30% ethanol. 4 ml of 2M ethanolic hydrazine hydrate solution are added and the mixture is stirred overnight at room temperature. The reaction mixture is acidified with 10 ml of 2N hydrochloric acid, warmed briefly and the precipitate is filtered off. The filtrate is evaporated and the residue is dissolved in water. A dilute sodium carbonate solution is added to the aqueous solution and the mixture is extracted with methylene chloride. The methylene chloride solution is dried over sodium sulfate and evaporated. 2.5 g of the title compound are obtained as a yellowish, amorphous residue. 3. (RS) -N-α- (2-naphthylsulfonylαlvcyl) -N ^ - (2.3.5.6-tetrachloropyridine-4-vn-α, γ-diaminobutyric acid piperidide

2 g of (R, S) -N-α- (2-naphthylsulfonylglycyl) -α, γ-diaminobutyric acid piperidide in absolute 20 ml. Dioxane dissolved. A solution of 1.4 g of 4-nitro-2,3,5,6-tetrachloropyridine and 0.6 ml of triethylamine in 10 ml of absolute is added with ice cooling and with stirring. Dioxane. The mixture is stirred for a further 3 hours at room temperature and the reaction mixture is then evaporated in vacuo. on. The residue is chromatographed for purification on a silica gel column (mobile phase: isohexane / ethyl acetate 1: 2). After evaporating the column fractions, 1.1 g of crystals with a melting point of 205 degrees Celsius are obtained. FAB-MS: M + H 648

Example 2

(R.S) -N- - (2-Naphthylsulfonylαlvcvn-N * ^ - (pyridine-4-vπ-α.γ-diaminobutyric acid piperidide

1 g of (R, S) -N-α- (2-naphthylsulfonylglycyl) -N * -y- (2,3,5,6-tetrachloropyridin-4-yl) - α, γ-diaminobutyric acid piperide in 20 ml Dissolved methanol and hydrogenated after adding 5 ml of 1M sodium methylate solution in the presence of 100 mg Pd / C (10%) catalyst. After the calculated amount of hydrogen has been taken up, the catalyst is filtered off and evaporated. The residue is chromatographed on a silica gel column. (Mobile solvent: methylene chloride / methanol 8: 2). The column fractions are evaporated and the residue is triturated with ether. 350 mg of the title compound are obtained. Mp: 135 degrees Celsius. FAB-MS: M + H 510.

Example 3

(R.S) -N-α- (4-toluenesutfonylαlvcvπ-N * ^ - (pyridine-4-vπ-α.v-diaminobutyric acid piperidide

The preparation was carried out analogously to Examples 1 and 2, except that in step 1 p-toluenesulfonylglycyl chloride was used instead of 2-naphthyisulfonylglycyl chloride. Mp of the titanium compound: 160 degrees Celsius (dec.). FAB-MS: M + H 474. Example 4

(RS) -N- - (2-naphthylsulfonyl) -N * ^ y (Pvπdin-4-yl) - .γ-diaminobutte ^"rsäure piperidide

The preparation was carried out analogously to Examples 1 and 2, except that in step 1 2-naphthylsulfonyl chloride was used instead of 2-naphthylsulfonyiglycyl chloride. The title compound was obtained as an amorphous substance. FAB-MS: M + H 453.

Example 5

(R.S) -N-α- (2-naphthylsulfonylqlvcvn-N-δ- (2.3.5.6-tetrachloropyridine-4-vn-α.δ-diaminovaleric acid piperidide

1. (R, S) -α-amino-δ-phthalimido-valeric acid

29.6 g of phthalic anhydride are heated together with 23.4 g of 5-aminovaleric acid to 190 degrees Celsius for 30 minutes. The δ-phthalimido-valeric acid residue obtained after cooling is recrystallized from aqueous ethanol. Mp .: 117 degrees Celsius. 47.3 g of this compound are mixed with 2 g of red phosphorus. 20.7 g of bromine are slowly added dropwise to this mixture while stirring. After the bromine has been added, the mixture is heated to 100 degrees Celsius for 2 hours and then allowed to cool. The residue is mixed with 200 ml of ice water and the mixture is stirred for an hour. The mixture is mixed with methylene chloride, the water phase is separated off and discarded. The methylene chloride phase is dried over sodium sulfate and evaporated. The crude α-bromo-δ-phthalimido-valeric acid obtained (53 g) is dissolved in 300 ml of dimethylformamide without further purification. 20.8 g of sodium azide are added to this solution and the mixture is stirred for 24 hours at room temperature. Then the solution i.Vak. evaporated, the residue dissolved in ethyl acetate, the solution washed with water, dried over sodium sulfate and evaporated. The α-azido-δ-phthalimido-valeric acid obtained is concentrated in a mixture of 240 ml of glacial acetic acid and 30 ml. Hydrochloric acid dissolved and hydrogenated as a catalyst after adding 2 g of platinum oxide. After the hydrogen uptake has ended, the catalyst is suctioned off and the filtrate is evaporated. The residue is dissolved in 50 ml of water and 12 ml of pyridine are added to the solution. The precipitate is suctioned off with Washed water and dried. 25 g (R, S) -α-amino-δ-phthalimido-valeric acid are obtained. Mp: 230 degrees Celsius.

2. (R, S) -4- (γ-phthalimidopropyl) -oxazolidin-2,5-dione 12 g (R.S) -α-amino- δ-phthalimido-valeric acid are absolute in 100 ml. Dioxane suspended. Phosgene is introduced into this suspension with stirring at 70 degrees Celsius until a clear solution has formed. The mixture is allowed to cool and the precipitate formed is filtered off with suction. Yield: 9.5g. MP: 235 degrees Celsius (dec.).

3. (R, S) -N-α- (2-naphthylsulfonylglycyl) -N-δ-phthaiimido-α-aminovaleric acid piperidide

The illustration was carried out analogously to stage 1 in Example 1, except that instead of (R, S) -4- (β-phthalimidoethyl) oxazoiidin-2,5-dione (R, S) -4- (γ-phthalimidopropyl) -oxazolidin-2,5-dione was used. The title compound was obtained as a white, amorphous solid.

4. (R, S) -N-α- (2-naphthylsulfonylglycyl) -α, δ-diaminovaleric acid piperidide The preparation was carried out analogously to step 2 in Example 1 using (R, S) -N-α- (2- Naphthylsulfonylglycyl) -δ-phthal-imido- -aminovaleriansäure- piperidide as starting material. The title compound was obtained as an amorphous solid.

5. (R, S) -N-α- (2-naphthylsulfonylglycyl) -N-δ- (2,3,5,6-tetrachloropyridin-4-yl) - α, δ-diaminovaleric acid piperidide

The preparation was carried out analogously to step 3 in Example 1 using R, SN-α- (2-naphthylsulfonylglycyl) -α, δ-di-aminovaleric acid piperidide as starting material. Mp of the title compound: 187 degrees Celsius (from methanol). FAB-MS: M + H 662. Example 6

(R.S) -N-α- (2-naphthylsulfonylqlvcyl) -N-δ- (pyridin-4-yl) -α, δ-diaminovalerianic acid piperidide

The preparation was carried out analogously to Example 2 using (RS) -N-α- (2-naphthylsulfonylglycyl) -N-δ- (2,3,5,6-tetrachloropyridin-4-yl) -α, δ-diamino-valeric acid as starting material. The title compound was obtained as a white, amorphous solid. FAB-MS: M + H 524.

Example 7

(R.S N- - (2-Naphthylsulfonylqlvcvn-N-ß- (2.3.5.6-tetra-chloro-pyridin-4-yl) -α.ß-diaminopropionic acid piperidide

1. (R, S) -N-α-N-ß-dibenzyloxycarbonyl-, ß-diaminopropionic acid

17.5 g of (R, S) -α, ß-diaminopropionic acid are suspended in 170 ml of water. The pH is adjusted to 9 by adding dilute sodium hydroxide solution, the substance going into solution. A solution of 53.5 ml of benzyl chloroformate in 300 ml of toluene is then added dropwise with stirring. The pH value is kept at 9 by simultaneous addition of dilute sodium hydroxide solution. After the addition of the benzyl chloroformate has ended, the mixture is stirred for a further 4 hours at room temperature and the solution is then acidified to pH 1 with dilute hydrochloric acid. The precipitate is filtered off, washed with water and dried. Yield: 38.3 g mp: 122 degrees Celsius.

2. (R, S) -4- (benzyloxycarbonylaminomethyl) oxazolidine-2,5-dione

25 g (R, S) -N-α, N-ß-dibenzyloxycarbonyl-α, ß-diaminopropionic acid are absolute in 250 ml. Chloroform dissolved. To do this, add 20 ml of thionyl chloride and heat the mixture to 50 degrees Celsius for 1 hour. Then it is evaporated to dryness, the residue is taken up in 100 ml of ethyl acetate and heated under reflux for 1 hour. Half evaporate, give 250 ml of absolute. Hexane and allows to crystallize. The crystals are suctioned off with absolute. Washed and dried hexane. Yield: 17.5 g. Mp: 128 degrees Celsius. 3. (R, S) -N-α- (2-naphthylsulfonylglycyl) -N-ß-benzyioxy-carbonyl-α, ß-diaminopropionic acid piperidide

1.2 g (R, S) -4-benzyloxycarbonylaminomethyloxazolidin-2,5-dione are absolute in 10 ml. Dimethylformamide dissolved and cooled to -50 degrees Celsius. A solution of 0.45 ml of piperidine and 0.5 ml of N-methylpiperidine in 10 ml of absolute is added to this solution with stirring. Methylene chloride. The mixture is allowed to come to room temperature and is stirred for a further 30 min. and then heats the reaction mixture to 60 degrees Celsius for 30 minutes. The mixture is cooled to room temperature and a solution of 1.31 g of 2-naphthylsulfonylglycyl chloride in 10 ml of methylene chloride is added dropwise with stirring. The mixture is stirred for a further 4 hours at room temperature, the solution is diluted with 100 ml of methylene chloride and washed with water. The methylene chloride phase is dried over sodium sulfate and evaporated. The residue is chromatographed on a silica gel column for purification. (Eluent: ethyl acetate / isohexane 1.5: 1). After evaporation of the corresponding column fractions, 1.45 g of a white solid are obtained. Mp: 148 degrees Celsius.

4. (R, S) -N-α- (2-naphthylsulfonylglycyl) -, ß-diaminopropionic acid piperidide hydrobromide

1.1 g (R, S) -N-α- (2-naphthylsulfonylglycyl) -N-β-benzyloxy-carbonyl-α, β-diaminopropionic acid are dissolved in 4 ml of a 33% solution of bromine water in glacial acetic acid. The mixture is stirred for another hour and then evaporated i.Vak. on. The residue is triturated with ether, suction filtered and dried. 0.9 g of the title compound is obtained as a white, amorphous solid.

5. (R, S) -N-α- (2-naphthylsulfonylglycyl) -N-β- (2,3,5,6-tetra-chloro-pyridin-4-yl) - α, β-diaminopropionic acid piperidide

0.6 g (R, S) -N-α- (2-naphthylsulfonyl) -glycyl-α, ß-diamino-propionic acid piperidide hydrobromide in 5 ml absolute. Dioxane dissolved. 0.4 g of 4-nitro-2,3,5,6-tetra-chloropyridine and 0.2 ml of triethylamine are added and the mixture is stirred overnight at room temperature. Then it is evaporated and the residue is chromatographed on a silica gel column (mobile solvent: methylene chloride / methanol 97.5: 2.5). The residue obtained after evaporating the column fractions is recrystallized from methanoi. Yield: 350 mg, mp: 189 degrees Celsius. FAB-MS: M + H 634. Example 8

(R.S) -N-α- (2-Naphthylsulfonylqlvcvn-N-ß- (pyridin-4-yl) - α.ß-diaminopropionic acid piperidide

300 mg (R, S) -N- - (2-naphthylsulfonylglycyl) -N-ß- (2,3,5,6-chloropyridin-4-yi) are dissolved in 15 ml of methanol and after the addition of 7 ml of 1 M sodium methylate solution and 200 mg Pd / C (10%) catalyst are hydrogenated. After the calculated amount of hydrogen has been taken up, the catalyst is filtered off and the filtrate is evaporated. The residue is chromatographed on silica gel (eluent: methylene chloride / methanol 8: 2 The acidic fractions are evaporated and the residue is triturated with ether, giving 200 mg of the title compound as colorless crystals, mp: 95 degrees Celsius, FAB-MS: M + H 496.

Example 9

(R) -N-α- (2-naphthylsulfonylqlvcyl) -N * ^ - (2.3.5.6-tetrachloropyridin-4-yl) -α.y -diaminobutyric acid piperidide

1. (R) -Z-glutamine piperidide

6 g (R) -Z-glutamine are dissolved in 60 ml absolute dioxane. For this purpose, 2.5 g of N-hydroxysuccinimide and 5 g of dicyclohexyldicarbodiimide are added and the mixture is then stirred for 20 hours at room temperature. The resulting precipitate is filtered off and discarded. The filtrate is mixed with 2.1 ml of piperidine and the mixture is stirred for 24 hours at room temperature. It sucks off any turbidity that may have arisen and the filtrate is concentrated. The residue is triturated with ethyl acetate and the crystals are filtered off with suction. 3.7 g of (R) -Z-glutamine piperidide are obtained. Mp .: 95 degrees Celsius.

2. (R) -N-a-benzyloxycarbonyl-α, γ-diaminobutyric acid piperidide

3.4 g of (R) -Z-glutamine piperidide are dissolved in a mixture of 30 ml of acetonitrile and 30 ml of water. 6.5 g of [bis (trifluoroacetoxy) iodo] benzene are added and the mixture is stirred overnight at room temperature. It is diluted with 200 ml of water, acidified to pH 1 with dilute hydrochloric acid and shaken out with ether. The aqueous phase is cooled with 10 N sodium hydroxide solution made alkaline and extracted with ethyl acetate. The ethyl acetate phase is dried over sodium sulfate and evaporated. 2.1 g of the title compound are obtained as an amorphous substance.

3. (R) -N-α-benzyloxycarbonyl-N-γ- (2,3,5,6-tetrachloropyridin-4-yl) -α, γ -diaminobutyric acid piperidide

1.9 g (R) -N-α-benzyloxycarbonyl-α, γ-diaminobutyric acid piperidide are absolute in 20 ml. Dioxane dissolved. For this purpose, 1.7 g of 4-nitro-2,3,5,6-tetrachloropyridine are added and the mixture is stirred for 3 hours at room temperature. The reaction mixture is then diluted with 300 ml of water and extracted with ethyl acetate. The ethyl acetate phase is dried over sodium sulfate and evaporated. The residue is chromatographed on a silica gel column for purification. (Eluent: ethyl acetate / isohexane 3: 1). After evaporating the column fractions, 1.9 g of the title compound are obtained as an oily substance.

4. (R) -N-γ- (2,3,5,6-tetrachloropyridin-4-yl) -α, γ-diaminobutyric acid piperidide hydrobromide

950 mg (R) -N-α-benzyioxycarbonyl-N-γ- (2,3,5,6-tetrachloropyridin-4-yl) -α, γ -diaminobutyric acid piperidide are dissolved in 2 ml of a 33% solution of hydrogen bromide dissolved in glacial acetic acid. The mixture is stirred overnight at room temperature and then i.Vac. evaporated. The residue is triturated with ether. 630 mg of the title compound with a melting point of 180 degrees Celsius are obtained.

5. (R) -N-α- (2-naphthylsulfonylglycyl) -N-γ- (2,3,5,6-tetrachloro-pyridin-4-yl) -α, γ-diaminobutyric acid piperidide

325 mg (R) -N-γ- (2,3,5,6-tetrachloropyridin-4-yl) -α, γ-diamino-butyric acid piperidide hydrobromide are absolute in 4 ml. Dissolved methylene chloride. 0.2 ml of N-methylmorpholine and 200 mg of 2-naphthylsulfonylglycyl chloride are added. The mixture is stirred for 2 hours at room temperature and then evaporated. The residue is chromatographed on a silica gel column. (Eluent: ethyl acetate / isohexane 2: 1). After evaporating the column fractions, 220 mg of the title compound with a melting point of 130 degrees Celsius are obtained. FAB-MS: M + H 648. Example 10

(R) -N-α- (2-Naphthylsulfonylglvcyl) -N-γ- (pyridin-4-yl) -α, γ-diaminobutyric acid piperidide

140 mg (R) -N-α- (2-naphthylsulfonylglycyl) -N - γ- (2,3,5,6-tetra-chloropyridin-4-yl) -α, γ -diaminobutyric acid piperidide are in 5 ml of methanol dissolved and hydrogenated after addition of 2 ml of 1M sodium methylate solution and 100 mg of Pd / C (10%) catalyst. After the calculated amount of hydrogen has been taken up, the catalyst is filtered off and evaporated. The residue is chromatographed on a silica gel column. (Mobile solvent: methylene chloride / methanol 8: 2). The residue obtained after evaporating the column fractions is triturated with ether and suction filtered. 50 mg of the title compound with a melting point of 148 degrees Celsius are obtained. FAB-MS: M + H 510. [a] D = +2.40 [ethanol].

Example 11

(S) -N-α- ( ^, 2-Naphthylsutfonylglvcyl) -N-γ- (pyridin-4-yl) - .γ- diaminobutyric acid piperidide

The title compound was prepared analogously to the reaction sequence described in Examples 9 and 10, except that (L) -Z-glutamine was used as the starting material instead of (R) -Z-glutamine. Mp: 148 degrees Celsius. FAB-MS: M + H 510. [a] D = -2.40 [ethanol].

Example 12

(R) -N-α- (Phenylsulfonylglvcyl) -N-Υ- (pyridin-4-yl) -α.v- diamino-butyric acid piperidide

The title compound was prepared analogously to the reaction sequence described in Examples 9 and 10, except that in step 5, phenylsulfonylglycyl chloride was used instead of 2-naphthylsulfonylglycyichloride. Mp .: 130 degrees Celsius. FAB-MS: M + H 460. Example 13

(R) -N- - (4-methoxy-phenylsulfonylglvcyl) -N- ^ y- (pyridin-4-yl) - α.γ-diaminobutyric acid piperidide

The title compound was prepared analogously to the reaction sequence described in Examples 9 and 10, except that in step 5 4-methoxyphenyisulfonylglycyl chloride was used instead of 2-naphthylsulfonyiglycyl chloride. Mp: 140 degrees Celsius. FAB-MS: M + H 490.

Example 14

(R) -N-α- (4-trifluoromethyl-phenylsulfonylglvcyl) -N-γ- (pyrid in-4-yl) -α, γ-diaminobutyric acid piperidide

The title compound was prepared analogously to the reaction procedure described in Examples 9 and 10, except that in step 5 4-trifluoromethylphenylsulfonylglycyl chloride was used instead of 2-naphthylsulfonylglycyl chloride. Mp: 180 degrees Celsius. FAB-MS: M + H 528. [a] D = +10.7 °.

Example 15

(R) -N- - (5.6.7.8-Tetrahvdronaphthalin-2-sutfonylqlvcylVN - ^ - (pyridin-4-yl) -α.v-diaminobutyric acid piperidide

The title compound was prepared analogously to the reaction sequence described in Examples 9 and 10, except that in stage 5 portions of 2-naphthylsulfonylglycyl chloride 5,6,7,8-tetrahydronaphtaline-2-sulfonylglycyl chloride were used. Mp: 120 degrees Celsius. FAB-MS: M + H 514. Example 16

(R) -N-α- (2-N-naphthylsulfonyl- (R) -alanyl) -N-γ- (pyridin-4-yl) -α.y -diaminobutyric acid piperidide

The title compound was prepared analogously to the reaction sequence described in Examples 9 and 10, except that in step 5 2-naphthylsulfonyl- (R) -alanyl chloride was used instead of 2-naphthylsulfonylglycyl chloride. Mp: 195 degrees Celsius. FAB-MS: M + H 524. [a] D = +77.6 °.

Example 17

(R) -N-α- (2-naphthylsulfonyl) - (S) -alanyl-N-v- (pyridine-4-vπ -α.v -diaminobutyric acid piperidide

The title compound was prepared analogously to the reaction sequence described in Examples 9 and 10, except that in step 5 2-naphthylsulfonyl- (S) -alanyl chloride was used instead of 2-naphthylsulfonyiglycyl chloride. Mp: amorphous substance. [a] D = -44.5 ° [ethanol]. FAB-MS: M + H 524.

Example 18

(R) -N-α- (4-nitro-phenylsutfonv0-qlvcyl-N-v- (pyridin-4-yl) -α.γ -diaminobutyric acid piperidide

1. (R) -N * ^ - (pyridin-4-yl) -α, γ-diaminobutyric acid piperidide

960 mg of (R) -N-γ- (2,3,5,6-tetrachloropyridin-4-yl) -α, γ-diamino-butyric acid piperidide hydrobromide are dissolved in 30 ml of methanol and after addition of 25 ml of 1 M sodium methylate solution and 200 mg Pd / C (10%) hydrogenated. After the calculated amount of hydrogen has been taken up, the catalyst is filtered off and the filtrate is evaporated. The residue is dissolved in water, the solution is adjusted to pH 10 by adding dilute sodium hydroxide solution and extracted with methylene chloride. The methylene chloride phase is over sodium sulfate dried and evaporated. 480 mg of the title compound are obtained as an amorphous residue.

2. (R) -N- - (4-nitrophenylsulfonylglycyl) -N-γ- (pyridin-4-yl) - α, γ-diaminobutyric acid piperidide

220 mg of N-γ- (pyridin-4-yl) -α, γ-diaminobutyric acid piperide are absolute in 5 ml. Dimethylformamide dissolved. 0.25 ml of N-methylmorpholine and 250 mg of 4-nitro-phenylsulfonyl-glycyl chloride are added. The mixture is stirred for 2 hours at room temperature and then evaporated in vacuo. on. The residue is chromatographed on silica gel for purification. (Eluent: methylene chloride / methanol 8: 2). After evaporating the column fractions, 180 mg of the title compound are obtained as an amorphous substance. FAB-MS: M + H 505.

Example 19

(R) -N-α- (3-nitrophenylsulfonylqlvcyl) -N-γ- (pyridin-4-yl) - α.y-diaminobutyric acid piperidide

The title compound was prepared analogously to step 2 in Example 18, except that 3-nitro-phenylsulfonyl-glycyl chloride was used instead of 4-nitro-phenyisulfonyl-glycyl chloride. Amorphous substance. FAB-MS: 505.

Example 20

(R) -N-α- (4-chlorophenylsulfonylqlvcyl) -N-γ- (pyridine-4-vπ- α.γ-diaminobutyric acid piperidide

The title compound was prepared analogously to step 2 in Example 18, except that 4-chlorophenylsulfonylglycyl chloride was used instead of 4-nitrophenylsulfonylglycyl chloride. Amorphous substance. FAB-MS: M + H 495. Example 21

( ^, R) -N-α- (Cvclohexylsulfonylqlvcyl) -N-γ- (pyridin-4-yl) -α, γ-diaminobutyric acid piperidide

The title compound was prepared analogously to the reaction sequence described in Examples 9 and 10, except that in step 5 cyclohexylsulfonyl chloride was used instead of 2-naphthylsulfonylglycyl chloride. Mp: 110 degrees Celcius. FAB-MS: M + H 466.

Example 22

(R) -N-α- (2-naphthylsutfonylqlvcyl) -N * ^ y- (pyridin-4-yl) - α, y-diaminobutyric acid- (4-methyl-piperidide)

The titite compound was prepared analogously to the reaction sequence described in Examples 9 and 10, except that homopiperidine was used instead of piperidine. Mp: 150 degrees Celsius. FAB-MS: M + H 524.

Example 23

(R) -N- -f2.2.5.7.8-pentamethyl-6-chromanylsulfonylqlvcvπ- N-γ- (pyridin-4-yl) -α * ^ - diaminobutyric acid piperidide

The title compound was prepared analogously to the reaction sequence described in Examples 9 and 10, except that instead of 2-naphthyisulfonylglycyl chloride, 2,2,5,7,8-pentamethyl-6-chromanylsulfonylglycyl chloride was used. FAB-MS: M + H 529. Example 24

(R) -N-α- (4-methoxy-2,3,6-trimethylphenylsulfonylglvcyl) - N-γ- (pyridin-4-yl) - -γ-diaminobutyric acid piperidide

The title compound was prepared analogously to the reaction sequence described in Examples 9 and 10, except that 4-methoxy-2,3,6-trimethylsuifonylglycyl chloride was used instead of 2-naphthylsulfonylglycylchloride. FAB-MS: M + H 532.

Example 25

(R N-α- (2-Naphthylsulfonyl- (S) -methyl-asparaqv0-N-Υ- (pyridin-4-yl) -α - ^ - diaminobutyric acid piperidide

The titite compound was prepared analogously to the reaction sequence described in Examples 9 and 10, except that 2-naphthylsulfonyl- (S) -methyl-asparaginyl chloride was used instead of 2-naphthylsulfonylglycyl chloride. FAB-MS: M + H 582.

Example 26

(R) -N-α- (2-naphthylsulfonyl- (S) -asparaqvh-N-y- (pyridin-4-yl) - -y-diaminobutyric acid piperidide

The title compound was prepared by alkaline hydrolysis of example 25. FAB-MS: M + H 568.

Example 27

(R) -N-α- (2-naphthylsulfonylglvcyl) -N-Υ- (pyridine-4-vπ-α, γ-diaminobutyric acid morpholide The title compound was prepared analogously to the reaction sequence described in Examples 9 and 10, except that morpholine was used instead of piperidine. FAB-MS: M + H 512.

Example 28

(R) -N-α- (2-Naphthylsutfonylazaqlvcv0-N-v- (pyridine-4-vD-α, γ-diaminobutyric acid piperidide

1.5 g of (R) -N-γ- (2,3,5,6, -Tetrachior-pyridin-4-yl) -α, γ-diaminobutyric acid piperidide are in 15 ml abs. Dimethylformamide dissolved. 1 g of N-tert.-butoxycarbonyl-N ^' - (4-nitrophenoxycarbonyl) hydrazine and 0.2 ml of diisopropylamine are added. The mixture is stirred for one hour at room temperature, then mixed with 200 ml of water and the precipitate is filtered off with suction. The precipitate is chromatographed on a silica gel column for purification. (Detergent: ethyl acetate / isohexane 2: 1). 1.4 g of crystals with a melting point of 120 ° C. are obtained. These are dissolved in 30 ml of a 1.2 molar solution of hydrobromic acid in glacial acetic acid and the solution is stirred for 2 hours at room temperature. It is evaporated off in vacuo, the residue is triturated with ether and suction filtered. The filter residue is dissolved in 10 ml pyridine without further purification. 1.2 g of 2-naphthalenesulfonic acid chloride are added and the mixture is stirred for 4 hours at room temperature. It is diluted with 50 ml of water and suction filtered. The residue is chromatographed on a silica gel column for purification. (Eluent: ethyl acetate / isohexane 2: 1). The oily residue obtained (1.1 g) is dissolved in 50 ml of methanol and, after addition of 20 ml of a 0.4 molar sodium methylate solution and 200 mg of Pd / C (10%) catalyst, hydrogenated. After the hydrogen uptake has ended, the catalyst is suctioned off and evaporated. The residue is taken up in water and extracted with ethyl acetate. The ethyl acetate phase is dried over sodium sulfate and evaporated. The residue is chromatographed on a kiesi column. (Eluent: acetic ester). 400 mg of the title compound are obtained as an amorphous substance. FAB-MS: M + H 511 Example 29:

Pharmacological test description

Thrombin time

Thrombin time is a test commonly used in clinical coagulation diagnostics. This parameter detects the thrombin effect on fibrinogen and the formation of clot. Thrombin inhibitors cause an increase in thrombin time.

To obtain the plasma, 9 parts of fresh blood from healthy donors were mixed with one part of sodium citrate solution (0.11 mol / l) and centrifuged at approx. 3000 rpm for 10 minutes at room temperature. The plasma was pipetted off and can be stored at room temperature for about 8 hours.

200 μl of citrate plasma were incubated in a spherical coaguiometer (KC10 from Amelung) at 37 ° C. for 2 minutes. 10 μl of dimethyl sulfoxide (DMSO) or a solution of the active substance in DMSO were added to 190 μl of pre-heated thrombin reagent (Boehringer Mannheim GmbH; contains approx. 3 U / ml horse thrombin and 0.0125 M Ca ⁺⁺ ). With the addition of this 200 μl solution to the plasma, a stopwatch was started and the point in time until coagulation started was determined. The thrombin time in the control measurements was approx. 24 seconds and was significantly extended by the active substances.

The following table shows the measured thrombin times in seconds as the difference to the control. The concentrations of the active substances in the final volume are 250 μM (TT250), 25 μM (TT25) and 2.5 μM (TT2.5).

Thrombin inhibition

The kinetic measurements were carried out in 0.1 M phosphate buffer, which contained 0.2 M sodium chloride and 0.5% polyethylene glycol 6000, at a pH = 7.5 and 25 ° C. with the substrate H- (D) -Phe-Pro-Arg-pNA; Kabi and human α-thrombin (Sigma, specific activity = 2150 NIH units / mg) were carried out in polystyrene semi-micro cuvettes in a total volume of 1 ml. In a preliminary test, it was determined with each active substance whether it inhibits thrombin quickly or slowly. For this purpose, the reaction was started once by adding 0.03 NIH units of thrombin to a 100 μM solution of the substrate and the active ingredient. In a second experiment, substrate was added to a 5 min. Incubated solution of the thrombin and the active ingredient. The increase in the concentration of p-nitroaniline with time was monitored spectroscopically (UV-VIS spectrophotometer Lambda-2 from Perkin-Elmer) at 405 nm for 12 minutes. Since the measurement curves obtained in both experiments were linear and parallel, the active substances in the following table are fast thrombin inhibitors. The inhibition constants Kj were then determined as follows. The substrate was used in the concentrations 100 μM, 50 μM, 30 μM, 20 μM, and one measurement without inhibitor and three measurements in the presence of different concentrations of the inhibitors listed in the following table were carried out for each substrate concentration. The reactions were started by adding thrombin. The increase in absorbance at 405 nm by the resulting p-nitroaniline was monitored over a period of 12 minutes. Measuring points (time vs. extinction) were transferred to a PC at intervals of 20 seconds. The velocities V ₀ (change in extinction per second; measurements without inhibitor) and Vj (measurements with inhibitor) were determined from the data by linear regression. Only the part of each measurement in which the substrate concentration had decreased by less than 15% was used. From a series of measurements (constant inhibitor concentration, variable substrate concentrations), K _m ^" and V _{max were} determined by a nonlinear fit to the equation

Finally, Kj was calculated from the entire series of measurements by a nonlinear fit to the equation

Vmax * [S] V =

K _m * (1 + [S] / Kj) + [S] The Michaei constant K _m was 3.8 ± 2 μM in all measurements.

The inhibition constants Kj of the active substances are given in the following table in the unit μM.

Inhibition of trypsin and plasmin

10 mg of bovine pancreatic trypsin (Sigma) was dissolved in 100 ml of 1 mM hydrochloric acid and kept in the refrigerator. 20 μl thereof were mixed with 980 μl 1 mM hydrochloric acid. 25 μl of this was used for each measurement. The measurement was carried out as described for thrombin. K _m = 45 µM. The substances listed in the following table do not inhibit trypsin (Kj> 400 μM).

The measurements with human plasmin (Sigma, 10 units) were carried out with the substrate S-2251 (H- (D) -Val-Leu-Lys-pNA, Kabi) as described for thrombin. 0.01 units of plasmin were used for each measurement. K _m = 250 µM. The substances listed in the following table do not inhibit plasmin (Kj> 400 μM).

Connection from TT250 TT25 TT2.5 Ki [μM]

Example thrombin

2 330 85 20 0.40

3 100 25 4 2.00

4 108 21 3 5.00

8 193 49 6 2.00

10 124 34 0.20

12 44 10 10.00

13 285 71 21 0.70

22 93 23 4 2.00

Claims

1. Compounds of formula I.

in the

R _{1 is} an aryl, a heteroaryl or a cycioalkyl group, which can be substituted if desired,

AS an amino acid,

n the numbers 0 or 1,

R ₂ and Rg are identical or different and form hydrogen atoms, alkyl, carboxyalkyl or alkoxycarbonylalkyl groups, or R ₂ and Rg together with the nitrogen atom to which they are attached form a heterocyclyl ring which, if desired, also contains a second heteroatom and is substituted by alkyl , Carboxy or alkoxycarbonyl groups can be substituted,

R ₄ and R _{5 are the} same or different and are hydrogen atoms or alkyl groups,

m the numbers 0, 1 or 2, Rg, R, Rs and Rg are identical or different and denote hydrogen atoms or halogen atoms,

and their physiologically tolerable salts, hydrates, solvates, racemates and optically active isomers.

2. Compounds of formula I according to claim 1, characterized in that Rl is a phenyl, naphthyl, tetrahydronaphthyl, pyridinyl, thienyl, cyclohexyl or chromanyl ring, which is optionally by Cj-Cß-alkyl, Ci-Cß Alkoxy or halogen groups is mono- or polysubstituted.

3. Compounds of formula I according to claim 1 or 2, characterized gekenn¬ characterized in that AS means glycine, azaglycine, alanine, glutamine, glutamate, asparagine or aspartate.

4. Compounds of formula I according to any one of claims 1-3, characterized in that n is the number 0 or 1.

5. Compounds of formula I according to any one of claims 1-4, characterized gekenn¬ characterized in that R ₂ and Rg are the same or different and independently of one another a Ci-Cß-alkyl, Ci-Cß-alkoxycarbonyl-Ci-Ce -alkyl- or carboxy- C -) - Cg-alkyl group, or together with the N atom to which they are attached, form a pyrrolidine, piperidine, homopiperidine, morpholine, thio morpholine or piperazine ring which optionally substitutes is by one or two C- | -C6-alkyl, carboxyl or Ci-Cß-alkoxycarbonyl groups.

6. Compounds of formula I according to any one of claims 1-5, characterized gekenn¬ characterized in that R ₄ and Rc are the same or different and represent hydrogen atoms or Cj-Cß-alkyl groups.

7. Compounds of formula I according to any one of claims 1-6, characterized gekenn¬ characterized in that Rg, R ₇ , Rg, Rg are the same or different and represent hydrogen, fluorine or chlorine atoms.

8. Compounds of formula I according to any one of claims 1-7, characterized gekenn¬ characterized in that Rl phenyl, 4-methylphenyl, 4-chlorophenyl, 4-methoxyphenyl, 1-naphthyl, 2-naphthyl, 5,6,7, 8-tetrahydro-2-naphthyl, 3-pyridinyl, 2-thienyl, cyclohexyl, 2nd , 2,5,7,8-pentamethyl-chroman-6-yl or 4-methoxy-2,3,6-trimethylphenyl,

n can be the numbers 0 or 1,

R ₂ and Rg are the same or different and are ethyl, ethoxycarbonylmethyl or carboxymethyl or together with the N atom to which they are attached form a pyrrolidine, piperidine, homopiperidine, morpholine, thiomorpholine or piperazine ring, which optionally one or two methyl, ethyl, propyl, butyl, carboxyl, methoxycarbonyl, ethoxycarbonyl or tert. Can carry butyloxy-carbonyl groups,

R ₄ and R _{5 are} identical or different and denote hydrogen atoms or methyl groups,

Rg, R _j , Rg, Rg are the same or different and denote hydrogen, fluorine or chlorine atoms.

A process for the preparation of compounds of formula I according to any one of claims 1-8, characterized in that in a manner known per se

a) a compound of formula II

O R-,

R _r SO ₂ - (AS) n - NH- R3

(CR ₄ R ₅ ) m (||),

H ₂ N in the AS, n and m have the meanings given above, with a compound of the general formula III,

in which Rg-R _{g is} halogen.

or

a compound of formula XI

in which R ₂ -Rg and m have the meanings given, with a compound of the general formula VIII

O

Rf S - X (VIII),

Ö

implement R. has the meaning given and X represents either a halogen atom or a radical of the general formula IX, Y

^R ιo (X), CH

mean in which R _{1 Q represents} one of the usual amino acid side chains,

and then, if desired, converting the compounds obtained into solvates, hydrates or physiologically tolerable salts and cleaving racemates into enantiomers.

10. Medicament containing at least one compound of formula I according to any one of claims 1 to 8 in addition to pharmacologically acceptable vehicles and auxiliaries.

11. Use of compounds of formula I according to one of claims 1 to 8 for the manufacture of medicaments for the treatment of thrombo-embolic diseases.